Protective Effect of Na+/H+ Exchange Inhibitor, SM-20550, on Impaired Mitochondrial Respiratory Function and Mitochondrial Ca2+ Overload in Ischemic/Reperfused Rat Hearts

Abstract

The aim of this study was to investigate whether a selective Na+/H+ exchange inhibitor, SM-20550, can modulate the mitochondrial respiratory function and mitochondrial Ca2+ content in isolated rat hearts subjected to 40 min of ischemia and 20 min of reperfusion. SM-20550 (10, 100 nM) was administered for 5 min prior to ischemia and for 20 min during the reperfusion period. At 20 min after reperfusion, treatment with SM-20550 (10, 100 nM) improved the recovery of left ventricular developed pressure and suppressed the rise in left ventricular end-diastolic pressure. Mitochondrial function, assessed by the state 3 oxygen respiration rate, respiratory control index, and oxidative phosphorylation rate, was significantly impaired after ischemia/reperfusion. Administration with SM-20550 (10, 100 nM) attenuated the impaired mitochondrial function, improving the state 3 respiration rate, respiratory control index, and oxidative phosphorylation rate. The mitochondrial Ca2+ content was significantly increased after ischemia/reperfusion but was suppressed by treatment with SM-20550 (10, 100 nM). A significant linear correlation was observed between the respiratory control index and mitochondrial Ca2+ content in the ischemic/reperfused hearts. In conclusion, SM-20550 improved the postischemic recovery of left ventricular function and concurrently protected mitochondrial function mediated by preventing mitochondrial Ca2+ overload.

Cariporide preserves mitochondrial proton gradient and delays ATP depletion in cardiomyocytes during ischemic conditions

“…In a recent study (31), pretreatment with the selective NHE inhibitor SM-20550 was associated with attenuated Ca 2ϩ overload in mitochondria obtained from rat hearts submitted to 40 min of ischemia and 20 min of reperfusion, a result in agreement with the protective effect of NHE inhibition against cell necrosis secondary to ischemia-reperfusion, but [Ca 2ϩ ] m during ischemia was not measured. Our observation that cariporide, at concentrations that have been consistently found cardioprotective in isolated cells (25,27) and intact myocardium in vivo (6,16), enhanced mitochondrial Ca 2ϩ accumulation during simulated ischemia may appear surprising.…”

Decreased Neuronal Death in Na+/H+Exchanger Isoform 1-Null Mice afterIn VitroandIn VivoIschemia

“…HOE 642 (7 M) delayed mitochondrial matrix acidification and slowed ATP depletion in cardiomyocytes during ischemic conditions despite enhanced mitochondrial Ca 2ϩ accumulation (Ruiz-Meana et al, 2003). The NHE inhibitor SM20550 attenuated Ca 2ϩ overload in rat myocardial mitochondria after ischemia and reperfusion (Yamamoto et al, 2002). It remains to be further clarified whether the HOE 642 (1 M)-mediated neuroprotection in the current study results from targeting of both cytoplasmatic NHE1 and mitochondrial NHEs or whether NHE1 Ϫ/Ϫ neurons exhibit altered mitochondrial Ca 2ϩ buffering activity.…”

Cariporide (HOE642), a Selective Na + -H + Exchange Inhibitor, Inhibits the Mitochondrial Death Pathway

“…Indeed, another NHE inhibitor, SM-20550, was reported to inhibit Na ϩ and H ϩ transport in mitochondria, 22 and it preserved mitochondrial respiratory function. 23 MitoK ATP channels have cardioprotective effects against ischemia/reperfusion injury. 24,25 The mitoK ATP channel opener, diazoxide, prevents apoptosis induced by oxidative stress in cultured cardiomyocytes.…”